Opioid receptors activation

It is well established that NF-kB signaling plays a critical role in inflammation and immunity. Understanding the mechanism of NF-kB involvement in opioid receptor activation and chemokine expression may provide a vital key to understanding this complex signaling network. However, the elucidation of molecular mechanisms following activation of the opioid receptor family could aid in the development of future therapeutics for immune system-related and inflammatory diseases, drug addiction and HIV infection. 

Knapp PE, Hauser KF (1996) p-Opioid receptor activation enhances DNA synthesis in immature oligodendrocytes. Brain Res 743 341-345... 

Figure 21.5 Mechanisms of opioid analgesia at the spinal level. Action potentials in nociceptive afferent fibres invade the terminal and by opening calcium channels (L, N and P-type) cause the release of glutamate and peptides that further transmit pain subsequent to activation of their postsynaptic receptors. Presynaptic opioid receptor activation (mu- and delta-mediated effects have been most clearly shown) opens potassium channels which hyperpolarise the terminal, so reducing transmitter release and inhibiting the postsynaptic neuron...

Ma GH, Miller R, Kuznestov A et al. Kappa-opioid receptor activates an inwardly rectifying K+ channel by a G protein-linked mechanism coexpression in Xenopus oocytes. Mol Pharmacol 1995 47 1035-1040. 

As described in Chapter 4, regulatory G proteins act as an intermediate link between receptor activation and the intracellular effector mechanism that ultimately causes a change in cellular activity. In the case of opioid receptors, these G proteins interact with three primary cellular effectors calcium channels, potassium channels, and the adenyl cyclase enzyme.27 At the presynaptic terminal, stimulation of opioid receptors activates G proteins that in turn inhibit the opening of calcium channels on the nerve membrane.65 Decreased calcium entry into the presynaptic terminal causes decreased neurotransmitter release because calcium influx mediates transmitter release at a chemical synapse. At the postsynaptic neuron, opioid receptors are linked via G proteins to potassium channels, and... 

Finnegan TF, Chen SR, Pan HL (2006) Mu opioid receptor activation inhibits GABAergic inputs to basolateral amygdala neurons through Kvl.1/1.2 channels. J Neurophysiol 95 2032-41 Fu LY, Acuna-Goycolea C, van den Pol (2004) Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms tonic depression of the hypothalamic arousal system. J Neurosd 24 8741-51... 

Rusin, K. I., Giovannucci, D. R., Stuenkel, E. L., and Moises, H. C. (1997). Kappa-opioid receptor activation modulates Ca2+ currents and secretion in isolated neuroendocrine nerve terminals. J. Neurosci. 17, 6565-6574. 

The promiscuity of the delta opioid receptor to regulate multiple effectors also is reflected in the ability of the receptor to induce GTP binding to all the G /G0 a subunits. By using either 32P-azidoanilido GTP to photoaffinity label the Ga subunits or cholera toxin to ADP-ribosylate the Gj/Go a subunits after their dissociation from the (S-y subunits, several reports have indicated that the delta opioid receptors could activate the Gj/G0 proteins with equal potency [22 24]. The ability of delta opioid receptor to activate G protein other than G /G0 was demonstrated by the coimmunoprecipitation of receptor with the recombinant Gz, which has 66% sequence homology with that of the G /G0 and which cannot be inactivated by PTX [25]. The ability of delta opioid receptor to interact with Gz presents a probable explanation for those observations that opioid receptor activities could not be blocked by PTX. We will review the delta opioid receptor activation of these G proteins and the mechanism for the subsequent effectors regulation separately. 

In the past, Ga subunits were considered to mediate the opioid receptor inhibition of the Ca2+ activities. The involvement of Gao was suggested initially by the injection of the a subunit into NG108-15 cells pretreated with PTX, thus restoring the delta opioid receptor activity [16]. This was later substantiated by the use of Gao-selective antisera [61]. Using antisense... 

The activation of Erkl/2 by opioid receptor has been shown to occur through the G(5y subunits in a Ras-dependent manner [101]. However, whether the delta opioid receptor activation of the Erkl/2 requires the receptor being internalized is controversial. Coscia and coworkers suggested that delta opioid receptor internalization is a prerequisite for the agonist activation of the Erkl/2 [102]. However, several laboratories have since reported that opioid receptor activation of Erkl/2 did not depend on the receptor internalization [103,104]. Dominant negative dynamin mutant that would block the agonist-induced receptor internalization would not attenuate the Erkl/2 stimulation. Such data support the observation that morphine could stimulate the Erkl/2 activity but could not induce receptor internalization [105], Thus, the delta opioid receptor stimulates the Erkl/2 activities prior to the receptor internalization processes. 

DELTA OPIOID RECEPTOR ACTIVATION OF G PROTEIN SUBTYPES... 

Dual inhibitors also demonstrate other therapeutical benefits. They reduced the coronary vasoconstriction in arthritic hearts in a rat model [101], and significantly decreased angiotensin II-induced contractions in human internal mammary artery [102], Opioid receptor activation can cause a presynaptic inhibition of neurotransmitter release mediated by LOX metabolites of arachidonic acid in midbrain neurons. The efficacy of opioids was enhanced synergistically by treatment of brain neurons with COX and LOX dual inhibitors. This report might lead to development of CNS analgesic medications involving combinations of lowered doses of opioids and COX/LOX dual inhibitors [103]. The COX and 5-LOX dual inhibitors also can prevent lens protein-induced ocular inflammation in both the early and late phases [104]. 

---